Megalencephalic leukoencephalopathy with subcortical cysts is a developmental disorder of the gliovascular unit

eLife

Virginie Mignon¹  Sonia Taïb²  Isabelle Brunet²  Sabrina Martin²  Armelle Rancillac³  Denis Vivien⁴  Mervé Yetim⁴  Audrey Chagnot⁴  Mickael Tanter⁵  Thomas Deffieux⁵  Vincent Hingot⁵  Rodrigo Alvear-Perez⁶  Anne-Cécile Boulay⁶  Xabier Elorza-Vidal⁶  Martine Cohen-Salmon⁶  Alice Gilbert⁷  Maryline Favier⁸  Aontoinette Gelot⁹  Raul Estevez^1,10  Salvatore Cisternino^1,11  Xavier Declèves^1,12  Bruno Saubaméa^1,13 

[1] Cellular and Molecular Imaging Facility, US25 INSERM, UMS3612 CNRS, Faculty of Pharmacy, University of Paris, Paris, France;Molecular Control of the Neurovascular Development Research Group, Center for Interdisciplinary Research in Biology (CIRB), College de France, Labex Memolife, Université PSL, Paris, France;Neuroglial Interactions in Cerebral Physiopathology Research Group, Center for Interdisciplinary Research in Biology (CIRB), College de France, Labex Memolife, Université PSL, Paris, France;Normandie University, UNICAEN, INSERM, GIP Cyceron, Institut Blood and Brain, Physiopathology and Imaging of Neurological Disorders, Caen, France;Physics for Medicine Paris, ESPCI Paris, PSL University, Paris, France;Physiology and Physiopathology of the Gliovascular Unit Research Group, Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS Research in Biology (CIRB), College de France, CNRS, Paris, France;Physiology and Physiopathology of the Gliovascular Unit Research Group, Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS Research in Biology (CIRB), College de France, CNRS, Paris, France;École doctorale Cerveau Cognition Comportement “ED3C” N°158, Pierre and Marie Curie University, Paris, France;Plateforme HistIM Institut Cochin, Paris, France;Service d’anatomie et cytologie pathologie de l’hôpital Armand Trousseau, Paris, France;Unitat de Fisiología, Departament de Ciències Fisiològiques, IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain;Centro de Investigación en Red de Enfermedades Raras (CIBERER), Barcelona, Spain;Université de Paris, Faculté de Santé, Paris, France;Université de Paris, Faculté de Santé, Paris, France;Biologie du médicament et toxicologie, Assistance Publique – hôpitaux de Paris, APHP, Hôpital Cochin, Paris, France;Université de Paris, Faculté de Santé, Paris, France;Cellular and Molecular Imaging Facility, US25 INSERM, UMS3612 CNRS, Faculty of Pharmacy, University of Paris, Paris, France;

关键词: MLC;    MLC1;    gliovascular unit;    astrocytes;    development;    Mouse;   

DOI  :  10.7554/eLife.71379

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Absence of the astrocyte-specific membrane protein MLC1 is responsible for megalencephalic leukoencephalopathy with subcortical cysts (MLC), a rare type of leukodystrophy characterized by early-onset macrocephaly and progressive white matter vacuolation that lead to ataxia, spasticity, and cognitive decline. During postnatal development (from P5 to P15 in the mouse), MLC1 forms a membrane complex with GlialCAM (another astrocytic transmembrane protein) at the junctions between perivascular astrocytic processes. Perivascular astrocytic processes along with blood vessels form the gliovascular unit. It was not previously known how MLC1 influences the physiology of the gliovascular unit. Here, using the Mlc1 knock-out mouse model of MLC, we demonstrated that MLC1 controls the postnatal development and organization of perivascular astrocytic processes, vascular smooth muscle cell contractility, neurovascular coupling, and intraparenchymal interstitial fluid clearance. Our data suggest that MLC is a developmental disorder of the gliovascular unit, and perivascular astrocytic processes and vascular smooth muscle cell maturation defects are primary events in the pathogenesis of MLC and therapeutic targets for this disease.

【 授权许可】

CC BY